Talazoparib enhances resection at DSBs and renders HR-proficient cancer cells susceptible to Polθ inhibition.

BACKGROUND AND PURPOSE: The PARP inhibitor (PARPi), Talazoparib (BMN673), effectively and specifically radiosensitizes cancer cells. Radiosensitization is mediated by a shift in the repair of ionizing radiation (IR)-induced DNA double-strand breaks (DSBs) toward PARP1-independent, alternative end-joining (alt-EJ). DNA polymerase theta (Polθ) is a key component of this PARP1-independent alt-EJ pathway and we show here that its inhibition can further radiosensitize talazoparib-treated cells. The purpose of the present work is to explore mechanisms and dynamics underpinning enhanced talazoparib radiosensitization by Polθ inhibitors in HR-proficient cancer cells. METHODS AND MATERIALS: Radiosensitization to PARPis, talazoparib, olaparib, rucaparib and veliparib was assessed by clonogenic survival. Polθ-proficient and -deficient cells were treated with PARPis and/or with the Polθ inhibitors ART558 or novobiocin. The role of DNA end-resection was studied by down-regulating CtIP and MRE11 expression using siRNAs. DSB repair was assessed by scoring γH2AX foci. The formation of chromosomal abnormalities was assessed as evidence of alt-EJ function using G2-specific cytogenetic analysis. RESULTS: Talazoparib exerted pronounced radiosensitization that varied among the tested cancer cell lines; however, radiosensitization was undetectable in normal cells. Other commonly used PARPis, olaparib, veliparib, or rucaparib were ineffective radiosensitizers under our experimental conditions. Although genetic ablation or pharmacological inhibition of Polθ only mildly radiosensitized cancer cells, talazoparib-treated cells were markedly further radiosensitized. Mechanistically, talazoparib shunted DSBs to Polθ-dependent alt-EJ by enhancing DNA end-resection in a CtIP- and MRE11-dependent manner - an effect detectable at low, but not high IR doses. Chromosomal translocation analysis in talazoparib-treated cells exposed to Polθ inhibitors suggested that PARP1- and Polθ-dependent alt-EJ pathways may complement, but also back up each other. CONCLUSION: We propose that talazoparib promotes low-dose, CtIP/MRE11-dependent resection and increases the reliance of irradiated HR-proficient cancer cells, on Polθ-mediated alt-EJ. The combination of Polθ inhibitors with talazoparib suppresses this option and causes further radiosensitization. The results suggest that Polθ inhibition may be exploited to maximize talazoparib radiosensitization of HR-proficient tumors in the clinic.

Survivorship program including long-term toxicities and quality-of-life development over 10 years in a randomized trial in operable stage III non-small-cell lung cancer (ESPATUE).

Over 40% stage-III non-small-cell lung cancer (NSCLC) patients (pts) experience 5-year survival following multimodality treatment. Nevertheless, little is known about relevant late toxicities and quality-of-life (QoL) in the further long-term follow-up. Therefore, we invited pts from our randomized phase-III trial (Eberhardt et al., Journal of Clinical Oncology 2015) after 10 years from diagnosis to participate within a structured survivorship program (SSP) including follow-up imaging, laboratory parameters, cardio-pulmonary investigations, long-term toxicity evaluations and QoL questionnaires. Of 246 pts initially accrued, 161 were considered potentially resectable following the induction therapy and were randomized (80 to arm A: definitive chemoradiation; 81 to arm B: definitive surgery; 85 not randomized for different reasons; group C). 31 from 37 pts still alive after 10 years agreed to the SSP (13 in A; 12 in B; 6 in C). Clinically relevant long-term toxicities (grade 3 and 4) were rarely observed with no signal favoring any of the randomization arms. Furthermore, available data from the global QoL analysis did not show a signal favoring any definitive locoregional approach (Mean QoL in SSP A pts: 56.41/100, B pts: 64.39/100) and no late decline in comparison to baseline and early 1-year follow-up. This is the first comprehensive SSP of very late survival follow-up reported in stage-III NSCLC treated within a randomized multimodality trial and it may serve as important baseline information for physicians and pts deciding for a locoregional treatment option.

Fibroblast Activation Protein-Directed Imaging Outperforms 18F-FDG PET/CT in Malignant Mesothelioma: A Prospective, Single-Center, Observational Trial.

The fibroblast activation protein (FAP) is highly expressed in tumor and stromal cells of mesothelioma and thus is an interesting imaging and therapeutic target. Previous data on PET imaging with radiolabeled FAP inhibitors (FAPIs) suggest high potential for superior tumor detection. Here, we report the data of a large malignant pleural mesothelioma cohort within a 68Ga-FAPI46 PET observational trial (NCT04571086). Methods: Of 43 eligible patients with suspected or proven malignant mesothelioma, 41 could be included in the data analysis of the 68Ga-FAPI46 PET observational trial. All patients underwent 68Ga-FAPI46 PET/CT, contrast-enhanced CT, and 18F-FDG PET/CT. The primary study endpoint was the association of 68Ga-FAPI46 PET uptake intensity and histopathologic FAP expression. Furthermore, secondary endpoints were detection rate and sensitivity, specificity, and positive and negative predictive values as compared with 18F-FDG PET/CT. Datasets were interpreted by 2 masked readers. Results: The primary endpoint was met, and the association between 68Ga-FAPI46 SUVmax or SUVpeak and histopathologic FAP expression was significant (SUVmax: r = 0.49, P = 0.037; SUVpeak: r = 0.51, P = 0.030).68Ga-FAPI46 and 18F-FDG showed similar sensitivity by histopathologic validation on a per-patient (100.0% vs. 97.3%) and per region (98.0% vs. 95.9%) basis. Per-region analysis revealed higher 68Ga-FAPI46 than 18F-FDG specificity (81.1% vs. 36.8%) and positive predictive value (87.5% vs. 66.2%). Conclusion: We confirm an association of 68Ga-FAPI46 uptake and histopathologic FAP expression in mesothelioma patients. Additionally, we report high sensitivity and superior specificity and positive predictive value for 68Ga-FAPI46 versus 18F-FDG.

The Role of Fibroblast Activation Protein in Glioblastoma and Gliosarcoma: A Comparison of Tissue, 68Ga-FAPI-46 PET Data, and Survival Data.

Despite their unique histologic features, gliosarcomas belong to the group of glioblastomas and are treated according to the same standards. Fibroblast activation protein (FAP) is a component of a tumor-specific subpopulation of fibroblasts that plays a critical role in tumor growth and invasion. Some case studies suggest an elevated expression of FAP in glioblastoma and a particularly strong expression in gliosarcoma attributed to traits of predominant mesenchymal differentiation. However, the prognostic impact of FAP and its diagnostic and therapeutic potential remain unclear. Here, we investigate the clinical relevance of FAP expression in gliosarcoma and glioblastoma and how it correlates with 68Ga-FAP inhibitor (FAPI)-46 PET uptake. Methods: Patients diagnosed with gliosarcoma or glioblastoma without sarcomatous differentiation with an overall survival of less than 2.5 y were enrolled. Histologic examination included immunohistochemistry and semiquantitative scoring of FAP (0-3, with higher values indicating stronger expression). Additionally, 68Ga-FAPI-46 PET scans were performed in a subset of glioblastomas without sarcomatous differentiation patients. The clinical SUVs were correlated with FAP expression levels in surgically derived tumor tissue and relevant prognostic factors. Results: Of the 61 patients who were enrolled, 13 of them had gliosarcoma. Immunohistochemistry revealed significantly more FAP in gliosarcomas than in glioblastomas without sarcomatous differentiation of tumor tissue (P < 0.0001). In the latter, FAP expression was confined to the perivascular space, whereas neoplastic cells additionally expressed FAP in gliosarcoma. A significant correlation of immunohistochemical FAP with SUVmean and SUVpeak of 68Ga-FAPI-46 PET indicates that clinical tracer uptake represents FAP expression of the tumor. Although gliosarcomas express higher levels of FAP than do glioblastomas without sarcomatous differentiation, overall survival does not significantly differ between the groups. Conclusion: The analysis reveals a significant correlation between SUVmean and SUVpeak in 68Ga-FAPI-46 PET and immunohistochemical FAP expression. This study indicates that FAP expression is much more abundant in the gliosarcoma subgroup of glioblastomas. This could open not only a diagnostic but also a therapeutic gap, since FAP could be explored as a theranostic target to enhance survival in a distinct subgroup of high-risk brain tumor patients with poor survival prognosis.

Cranioencephalic functional lymphoid units in glioblastoma.

The ecosystem of brain tumors is considered immunosuppressed, but our current knowledge may be incomplete. Here we analyzed clinical cell and tissue specimens derived from patients presenting with glioblastoma or nonmalignant intracranial disease to report that the cranial bone (CB) marrow, in juxtaposition to treatment-naive glioblastoma tumors, harbors active lymphoid populations at the time of initial diagnosis. Clinical and anatomical imaging, single-cell molecular and immune cell profiling and quantification of tumor reactivity identified CD8+ T cell clonotypes in the CB that were also found in the tumor. These were characterized by acute and durable antitumor response rooted in the entire T cell developmental spectrum. In contrast to distal bone marrow, the CB niche proximal to the tumor showed increased frequencies of tumor-reactive CD8+ effector types expressing the lymphoid egress marker S1PR1. In line with this, cranial enhancement of CXCR4 radiolabel may serve as a surrogate marker indicating focal association with improved progression-free survival. The data of this study advocate preservation and further exploitation of these cranioencephalic units for the clinical care of glioblastoma.

C-reactive protein as robust laboratory value associated with prognosis in patients with stage III non-small cell lung cancer (NSCLC) treated with definitive radiochemotherapy.

To evaluate the prognostic value of biomarkers from peripheral blood obtained as routine laboratory assessment for overall survival in a cohort of stage III non-small cell lung cancer (NSCLC) patients treated with definitive radiochemotherapy at a high-volume cancer center. Seven blood biomarkers from 160 patients treated with definitive radiochemotherapy for stage III NSCLC were analyzed throughout the course treatment. Parameters were preselected using univariable and multivariable proportional hazards analysis and were assessed for internal validity using leave-one-out cross validation. Cross validated classifiers including biomarkers in addition to important clinical parameters were compared with classifiers containing the clinical parameters alone. An increased C-reactive protein (CRP) value in the final week of radiotherapy was found as a prognostic factor for overall survival, both as a continuous (HR 1.099 (1.038-1.164), p < 0.0012) as well as categorical variable splitting data at the median value of 1.2 mg/dl (HR 2.214 (1.388-3.531), p < 0.0008). In the multivariable analysis, the CRP value-maintained significance with an HR of 1.105 (1.040-1.173) and p-value of 0.0012. The cross validated classifier using CRP at the end of radiotherapy in addition to clinical parameters separated equally sized high and low risk groups more distinctly than a classifier containing the clinical parameters alone (HR = 2.786 (95% CI 1.686-4.605) vs. HR = 2.287 (95% CI 1.407-3.718)). Thus, the CRP value at the end of radiation therapy has successfully passed the crucial cross-validation test. The presented data on CRP levels suggests that inflammatory markers may become increasingly important during definitive radiochemotherapy, particularly with the growing utilization of immunotherapy as a consolidation therapy for stage III NSCLC.

Prognostic factors for surgical treatment of radiation-induced scleral necrosis after brachytherapy for uveal melanoma.

PURPOSE: Radiation-induced scleral necrosis (RISN) is a less frequent complication of brachytherapy for uveal melanoma, and may require surgical treatment in selected cases. We aimed to identify the prognostic factors for RISN treatment. METHODS: All patients with brachytherapy for uveal melanoma treated at our institution between 01/1999 and 12/2016 who developed RISN were followed until 02/2021. Various parameters were evaluated through univariable and multivariable Cox regression analysis. The surgical intervention due to RISN was the principal outcome event of this study. RESULTS: Of 115 patients in the final cohort, 51 individuals (44%) underwent RISN treatment (conjunctival revision [n = 2], patching [n = 46] or enucleation [n = 3]) at median 1.80 months after RISN occurrence. Significant RISN characteristics were summarized into a novel RISN severity scale - Grade I: largest diameter ≤ 5 mm and no progression; Grade II: largest diameter > 5 mm or any progression during the follow-up; Grade III: presence of uveal prolapse; and Grade IV: leakage through open eyewall perforation. In the multivariable analysis, the RISN severity scale (aHR = 2.37 per grade increase, p = 0.01) and the time between brachytherapy and RISN occurrence (<15 months, aHR = 6.33, p < 0.0001) were independently associated with the study endpoint. The RISN severity scale showed high diagnostic accuracy for prediction of RISN treatment (AUC = 0.869). CONCLUSIONS: In our series, about the half of RISN cases underwent surgical treatment. The presented novel severity scale for RISN might become a helpful tool for clinical management of individuals with RISN. We recommend external validation of the diagnostic accuracy of the presented scale.

Prognostic Implications of 68Ga-FAPI-46 PET/CT-Derived Parameters on Overall Survival in Various Types of Solid Tumors.

Tumoral fibroblast activation protein expression is associated with proliferation and angiogenesis and can be visualized by PET/CT. We examined the prognostic value of [68Ga]Ga-fibroblast activation protein inhibitor (FAPI) (68Ga-FAPI)-46 PET/CT for different tumor entities in patients enrolled in 2 prospective imaging studies (NCT05160051, n = 30; NCT04571086, n = 115). Methods: Within 4 wk, 145 patients underwent 68Ga-FAPI-46 and [18F]FDG (18F-FDG) PET/CT. The association between overall survival (OS) and sex, age, tumor entity, total lesion number, highest SUVmax, and the presence of each nodal, visceral, and bone metastasis was tested using univariate Cox regression analysis. Multivariate analyses were performed for prognostic factors with P values of less than 0.05. Results: In the univariate analysis, shorter OS was associated with total lesion number and the presence of nodal, visceral, and bone metastases on 68Ga-FAPI-46 PET/CT (hazard ratio [HR], 1.06, 2.18, 1.69, and 2.05; P < 0.01, < 0.01, = 0.04, and = 0.02, respectively) and 18F-FDG PET/CT (HR, 1.05, 2.31, 1.76, and 2.30; P < 0.01, < 0.01, = 0.03, and < 0.01, respectively) and with SUVmax on 68Ga-FAPI-46 PET/CT (HR, 1.03; P = 0.03). In the multivariate analysis, total lesion number on 68Ga-FAPI-46 PET/CT was an independent risk factor for shorter OS (HR, 1.05; P = 0.02). In patients with pancreatic cancer, shorter OS was associated with total lesion number on 68Ga-FAPI-46 PET/CT (HR, 1.09; P < 0.01) and bone metastases on 18F-FDG PET/CT (HR, 31.39; P < 0.01) in the univariate analysis and with total lesion number on 68Ga-FAPI-46 PET/CT (HR, 1.07; P = 0.04) in the multivariate analyses. In breast cancer, total lesion number on 68Ga-FAPI-46 PET/CT (HR, 1.07; P = 0.02), as well as bone metastases on 18F-FDG PET/CT (HR, 9.64; P = 0.04), was associated with shorter OS in the univariate analysis. The multivariate analysis did not reveal significant prognostic factors. In thoracic cancer (lung cancer and pleural mesothelioma), the univariate and multivariate analyses did not reveal significant prognostic factors. Conclusion: Disease extent on 68Ga-FAPI-46 PET/CT is a predictor of short OS and may aid in future risk stratification by playing a supplemental role alongside 18F-FDG PET/CT.

Randomized Trial of Prostate-Specific Membrane Antigen PET/CT Before Definitive Radiotherapy for Unfavorable Intermediate- and High-Risk Prostate Cancer (PSMA-dRT Trial).

This multicenter randomized phase III trial (NCT04457245) evaluated the effect of performing prostate-specific membrane antigen (PSMA) PET/CT before definitive radiotherapy. Methods: Men with unfavorable intermediate- or high-risk prostate cancer were randomized 1.08:1 between receiving and not receiving a PSMA PET/CT scan before definitive radiotherapy. All other imaging modalities were allowed in the control arm. The primary endpoint was 5-y progression-free survival. Results: Fifty-four men were randomized between November 2020 and December 2021 (PSMA PET/CT, n = 25; control, n = 29). The trial closed early after approval and insurance coverage of PSMA PET/CT. In the PSMA PET/CT arm, 14 patients had localized disease (miT2b-cN0M0), 6 had locally advanced disease (miT3a-bN0M0), 3 had regional metastasis (miN1M0), and 1 had distant metastasis (miM1b). Four patients were upstaged. Conclusion: PSMA PET/CT upstaged 17% of patients, which allowed for more accurate radiotherapy planning. Unfortunately, this trial closed early before completion of target enrollment (54/316, 17%) and was underpowered to assess the effect of PSMA PET/CT on progression-free survival.

Long-Term Survival in Patients with Oligometastatic Non-Small Cell Lung Cancer by a Multimodality Treatment-Comparison with Stage III Disease.

Background: In patients with oligometastatic NSCLC, a cT3-cT4 primary tumor or an cN2/cN3 lymph node status was reported to be associated with unfavorable outcome. The aim of this study was to assess the importance of definitive or neoadjuvant thoracic radiochemotherapy for long-term outcome of these patients in order to find more appropriate treatment schedules. Methods: Analysis of the West Cancer Centre (WTZ) institutional database from 08/2016 to 08/2020 was performed. Patients with primary synchronous OMD, all without actionable driver mutations, who received definitive thoracic radiochemotherapy (RCT) or neoadjuvant RCT followed by surgery (trimodality treatment) were included. Survival outcome is compared with stage III NSCLC. Results: Altogether, 272 patients received concurrent radiochemotherapy. Of those, 220 presented with stage III (158 with definitive RCT, 62 with trimodality approach). A total of 52 patients had OMD patients with cT3/cT4 or cN2/cN3 tumors. Overall survival (OS) at five years for OMD patients was 28.3% (95%-CI: 16.4-41.5%), which was not significantly different from OS of patients with stage III NSCLC treated with definitive or neoadjuvant RCT (34.9% (95%-CI: 27.4-42.8%)). However, the PFS of OMD patients at five years or last follow-up was significantly worse than that of stage III patients (13.0% vs. 24.3%, p = 0.0048). The latter was due to a higher cumulative incidence of distant metastases in OMD patients (50.2% vs. 20.4% at 48 months, p < 0.0001) in comparison to stage III patients. A cross-validated classifier that included severe comorbidity, ECOG performance status, gender and pre-treatment serum CRP level as the most important factors in the univariable analysis, was able to divide the OMD patient group into two equally sized groups with a four-year survival rate of 49.4% in the good prognosis group and 9.9% in the poor prognosis group (p = 0.0021). Laboratory chemistry and clinical parameters, in addition to imaging and high-precision therapies, can help to predict and improve prognosis. Conclusions: A multimodality treatment approach and local metastases-directed therapy in addition to chemoimmunotherapy can lead to good long-term survival in patients with cT3/cT4 or cN2/cN3 OMD NSCLC without severe comorbidities and in good performance status and is therefore recommended.

Tumor- and Radiation-Related Complications after Ruthenium-106 Brachytherapy in Small to Medium Uveal Melanomas (Part 1).

PURPOSE: The purpose of this study was to analyze tumor-related complications after ruthenium-106 brachytherapy in patients with uveal melanoma, with respect to local tumor control, insufficient radiation response, enucleation, and metastasis rate. PATIENTS/METHODS AND MATERIALS: This retrospective study included 608 patients treated consecutively with ruthenium-106 brachytherapy between January 2008 and December 2010 at the Department of Ophthalmology, University Hospital Essen. The occurrence of radiation-induced results was analyzed by estimating the risk by applying the Kaplan-Meier method, i.e., the "time to event" analysis. The Cox model test was used for the univariate and multivariate risk factor analyses. The median follow-up was 51 months after primary treatment. RESULTS: Tumor recurrence was found in 21 patients (3.5%) and repeated treatment due to insufficient effect after the initial ruthenium-106 brachytherapy was performed in 40 patients (6.6%). The 5-year cumulative risk of recurrence was 4.0% and that of insufficient effect was 7.3%. Thirteen patients (2.1%) underwent a secondary enucleation; 8 because of a local recurrence and 5 because of severe post-brachytherapy complications. The cumulative enucleation risk was 2.3% after 5 years and 2.9% after 10 years, corresponding to eye preservation of 97.7 and 97.1%, respectively. In forty-two patients (7.2%), metastatic disease was diagnosed during the follow-up. The metastatic rate as calculated by the Kaplan-Meier method was 9.0, and 13.1% at 5 and 10 years, respectively. CONCLUSION: Our study demonstrated that ruthenium-106 brachytherapy is an excellent treatment option for achieving local tumor control and eye preservation in well-selected patients. The metastatic rate is in agreement with that of previous studies analyzing small to medium size uveal melanomas.

Treatment-Related Complications and Functional Results after Ruthenium-106 Brachytherapy in Small to Medium Size Uveal Melanomas (Part 2).

PURPOSE: To analyze the treatment-related complications after ruthenium-106 brachytherapy in patients with uveal melanoma in terms of radiation-induced optic neuropathy, maculopathy and retinopathy, radiation-related vitreous hemorrhage, and retinal detachment, as well as secondary glaucoma and radiogenic cataract. In addition, the course of visual acuity was analyzed. PATIENTS/METHODS AND MATERIALS: This retrospective study included 608 patients treated with ruthenium-106 brachytherapy between January 2008 and December 2010 at the Department of Ophthalmology, University Hospital Essen. The follow-up time was 11 years. The occurrence of the radiation-induced complications was analyzed using the Kaplan-Meier method. Cox regression was used for univariate and multivariate risk factor analyses. Hazard ratios were calculated for each variable. RESULTS: Regarding the complications, 34% (N = 207) of the patients had no reported side effects or complications during follow-up. Radiation optic neuropathy was observed in 18.8% (N = 114) of the patients, with a median time to onset of 16 months (range: 3 - 78 months). Radiation maculopathy occurred in 8.2% (N = 50) after a median time of 17 months (range: 3 - 67 months). Radiation retinopathy was observed in 20.1% (N = 122), with a median time to onset of 21 months (range: 6 - 67 months). Secondary glaucoma developed in 9.7% of the patients (N = 53) and radiogenic cataract in 46.8% (N = 227). Vitreous hemorrhage (11.8%, N = 72) and scleral necrosis (2.1%, N = 13) occurred relatively rarely. CONCLUSION: The observed radiogenic complication rate is comparable with that reported in previous studies.

Diagnostic Accuracy of 68Ga-FAPI Versus 18F-FDG PET in Patients with Various Malignancies.

To assess the diagnostic accuracy of 68Ga-labeled fibroblast activation protein inhibitor (FAPI) and 18F-labeled FDG PET for the detection of various tumors, we performed a head-to-head comparison of both imaging modalities across a range of tumor entities as part of our ongoing 68Ga-FAPI PET observational trial. Methods: The study included 115 patients with 8 tumor entities who received imaging with 68Ga-FAPI for tumor staging or restaging between October 2018 and March 2022. Of those, 103 patients received concomitant imaging with 68Ga-FAPI and 18F-FDG PET and had adequate lesion validation for accuracy analysis. Each scan was evaluated for the detection of primary tumor, lymph nodes, and visceral and bone metastases. True or false positivity and negativity to detected lesions was assigned on the basis of histopathology from biopsies or surgical excision, as well as imaging validation. Results: 68Ga-FAPI PET revealed higher accuracy than 18F-FDG PET in the detection of colorectal cancer (n = 14; per-patient, 85.7% vs. 78.6%; per-region, 95.6% vs. 91.1%) and prostate cancer (n = 22; per-patient, 100% vs. 90.9%; per-region, 96.4% vs. 92.7%). 68Ga-FAPI PET and 18F-FDG PET had comparable per-patient accuracy in detecting breast cancer (n = 16, 100% for both) and head and neck cancers (n = 10, 90% for both modalities). 68Ga-FAPI PET had lower per-patient accuracy than 18F-FDG PET in cancers of the bladder (n = 12, 75% vs. 100%) and kidney (n = 10, 80% vs. 90%), as well as lymphoma (n = 9, 88.9% vs. 100%) and myeloma (n = 10, 80% vs. 90%). Conclusion: 68Ga-FAPI PET demonstrated higher diagnostic accuracy than 18F-FDG PET in the diagnosis of colorectal cancer and prostate cancer, as well as comparable diagnostic performance for cancers of the breast and head and neck. Accuracy and impact on management will be further assessed in an ongoing prospective interventional trial (NCT05160051).

Surgical Outcome After Treatment of Radiation-Induced Scleral Necrosis in Patients With Uveal Melanoma.

PURPOSE: Surgical repair might be required in patients with uveal melanoma (UM) that develop advanced forms of radiation-induced scleral necrosis (RISN). In this monocentric long-term observational study, we aimed at analyzing the treatment outcome after RISN surgery. METHODS: All consecutive cases with UM who underwent surgical intervention for RISN between 1999 and 2020 were included. Achievement of the tectonic stability and evaluation of incidence and the risk factors for a repetitive patch surgery (RPS) were the main endpoints. RESULTS: The final analysis included 57 patients (mean age: 58.7 years; 63.2% female patients), where 55 individuals underwent a patch grafting, and 2 cases were treated with conjunctival reconstructive surgery. The mean follow-up time after grafting was 38.5 months (0.03-221.1 months). Tectonic stability was achieved in 56 (98.3%) patients. Scleral graft (38/55, 69.1%) was the most frequent patching material, followed by Tutopatch (7/55, 12.7%), corneal graft (7/55, 12.7%), dura graft (2/55, 3.6%), and fascia lata (FL) graft (1/55, 1.8%). Eleven patients (20%) underwent RPS after the mean time of 12.9 months (0.3-50.3 months). In the final multivariate Cox regression analysis, the use of Tutopatch (5/7; 71.4%, adjusted hazard ratio = 4.66, P = 0.044) and RISN progression after patch grafting (9/11; 81.8%, adjusted hazard ratio = 9.67, P = 0.008) were independent risk factors for RPS. CONCLUSIONS: RISN surgery maintains long-term tectonic stability in most of the cases underwent surgical repair for RISN after brachytherapy for UM. Depending on graft material and, particularly, further RISN progression, an RPS might be necessary in certain cases.

The value of subcutaneous xenografts for individualised radiotherapy in HNSCC: Robust gene signature correlates with radiotherapy outcome in patients and xenografts.

PURPOSE: To assess the robustness of prognostic biomarkers and molecular tumour subtypes developed for patients with head and neck squamous cell carcinoma (HNSCC) on cell-line derived HNSCC xenograft models, and to develop a novel biomarker signature by combining xenograft and patient datasets. MATERIALS AND METHODS: Mice bearing xenografts (n = 59) of ten HNSCC cell lines and a retrospective, multicentre patient cohort (n = 242) of the German Cancer Consortium-Radiation Oncology Group (DKTK-ROG) were included. All patients received postoperative radiochemotherapy (PORT-C). Gene expression analysis was conducted using GeneChip Human Transcriptome Arrays. Xenografts were stratified based on their molecular subtypes and previously established gene classifiers. The dose to control 50 % of tumours (TCD50) was compared between these groups. Using differential gene expression analyses combining xenograft and patient data, a gene signature was developed to define risk groups for the primary endpoint loco-regional control (LRC). RESULTS: Tumours of mesenchymal subtype were characterized by a higher TCD50 (xenografts, p < 0.001) and lower LRC (patients, p < 0.001) compared to the other subtypes. Similar to previously published patient data, hypoxia- and radioresistance-related gene signatures were associated with high TCD50 values. A 2-gene signature (FN1, SERPINE1) was developed that was prognostic for TCD50 (xenografts, p < 0.001) and for patient outcome in independent validation (LRC: p = 0.007). CONCLUSION: Genetic prognosticators of outcome for patients after PORT-C and subcutaneous xenografts after primary clinically relevant irradiation show similarity. The identified robust 2-gene signature may help to guide patient stratification, after prospective validation. Thus, xenografts remain a valuable resource for translational research towards the development of individualized radiotherapy.

Adaptation Time as a Determinant of the Dosimetric Effectiveness of Online Adaptive Radiotherapy for Bladder Cancer.

Interfraction anatomic deformations decrease the precision of radiotherapy, which can be improved by online adaptive radiation therapy (oART). However, oART takes time, allowing intrafractional deformations. In this study on focal radiotherapy for bladder cancer, we analyzed the time effect of oART on the equivalent uniform dose in the CTV (EUDCTV) per fraction and for the accumulated dose distribution over a treatment series as measure of effectiveness. A time-dependent digital CTV model was built from deformable image registration (DIR) between pre- and post-adaptation imaging. The model was highly dose fraction-specific. Planning target volume (PTV) margins were varied by shrinking the clinical PTV to obtain the margin-specific CTV. The EUDCTV per fraction decreased by-4.4 ± 0.9% of prescribed dose per min in treatment series with a steeper than average time dependency of EUDCTV. The EUDCTV for DIR-based accumulated dose distributions over a treatment series was significantly dependent on adaptation time and PTV margin (p < 0.0001, Chi2 test for each variable). Increasing adaptation times larger than 10 min by five minutes requires a 1.9 ± 0.24 mm additional margin to maintain EUDCTV for a treatment series. Adaptation time is an important determinant of the precision of oART for one half of the bladder cancer patients, and it should be aimed at to be minimized.

Recurrent prostate cancer: combined role for MRI and PSMA-PET in 68Ga-PSMA-11 PET/MRI.

OBJECTIVES: To investigate the specific strengths of MRI and PET components in 68Ga-PSMA-11 PET/MRI for staging of patients with biochemically recurrent prostate cancer (PCa). METHODS: Patients with biochemical recurrence of PCa and contrast-enhanced whole-body 68Ga-PSMA-11 PET/MRI including a dedicated pelvic multiparametric MRI were included in this retrospective study. Imaging datasets of MRI and PET were evaluated separately regarding local PCa recurrence (Tr), pelvic lymph node metastases (N1), distant lymph node metastases (M1a), bone metastases (M1b), and soft tissue metastases (M1c) according to PROMISE version 1. Data evaluation was performed patient- and region-/lesion-based. Cox regression revealed a PSA of 1.69 ng/mL as a cut-off for subgroup analysis. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were evaluated for each image component. Differences in staging accuracy were assessed using the Wilcoxon and McNemar test. RESULTS: Altogether 102 patients (mean aged 68 ± 8 years, median PSA 1.33 ng/mL) were included. PCa was found in 70/102 (68%) patients. Accuracy of MRI in the detection of Tr, N1, M + , M1a, and M1b was 100%, 79%, 90%, 97%, and 95% for PSA < 1.69 ng/mL and 100%, 87%, 87%, 91%, and 96% for PSA > 1.69 ng/mL. Accuracy of 68Ga-PSMA-11 PET was 93%, 97%, 93%, 98%, and 100% for PSA < 1.69 ng/mL and 87%, 91%, 96%, 100%, and 96% for PSA > 1.69 ng/mL. CONCLUSIONS: Combined assessment of 68Ga-PSMA-11 PET/MRI improves tumor localization in men with biochemical recurrence. The MRI detected local recurrence of PCa more often whereas 68 Ga-PSMA-11 PET detected lymph node metastases more often, especially for PSA < 1.69 ng/mL. CLINICAL RELEVANCE STATEMENT: This study gives a scientific baseline to improve the understanding and reading of 68Ga-PSMA-11 PET/MRI imaging in patients with biochemically recurrent PCa by showing the specific strength of each imaging component. KEY POINTS: • Combining the individual modality strengths of 68Ga-PSMA-11 PET/MRI improves tumor localization in men with biochemical recurrence of prostate cancer. • MRI component of 68 Ga-PSMA-11 PET/MRI shows its strength in detecting local recurrence of prostate cancer, especially at PSA < 1.69 ng/mL. • 68 Ga-PSMA-11 PET component shows its strength in detecting local and distant lymph node metastases, especially at PSA < 1.69 ng/mL.

Impact of Modern Low Dose Involved Site Radiation Therapy on Normal Tissue Toxicity in Cervicothoracic Non-Hodgkin Lymphomas: A Biophysical Study.

This biophysical study aimed to determine fitting parameters for the Lyman-Kutcher-Burman (LKB) dose-response model for normal tissue complication probability (NTCP) calculations of acute side effects and to investigate the impact of reduced radiation doses on the probability of their occurrence in supradiaphragmatic non-Hodgkin lymphoma (NHL) irradiation. A cohort of 114 patients with NHL in the cervicothoracic region, treated between 2015 and 2021 at the University Hospitals of Münster, Hamburg, and Essen, with involved site radiation therapy (ISRT), were included. Among them, 68 patients with aggressive NHL (a-NHL) received consolidative radiation therapy with 24-54 Gy following (R-)CHOP chemotherapy. Additionally, 46 patients with indolent NHL (i-NHL) underwent radiotherapy with 22.5-45.0 Gy. Two treatment plans were prospectively created for each patient (a-NHL: 30.0/40.0 Gy; i-NHL: 24.0/30.0 Gy). NTCP were then calculated using the optimized LKB model. The adapted dose-response models properly predicted the patient's probability of developing acute side effects when receiving doses ≤ 50 Gy. In addition, it was shown that reduced radiation doses can influence the NTCP of acute side effects depending on the aggressiveness of NHL significantly. This study provided a foundation to prospectively assess the probability of adverse side effects among today's reduced radiation doses in the treatment of NHL.

Pneumonectomy for Primary Lung Tumors and Pulmonary Metastases: A Comprehensive Study of Postoperative Morbidity, Early Mortality, and Preoperative Clinical Prognostic Factors.

BACKGROUND: Pneumonectomy is a major surgical resection that still remains a high-risk operation. The current study aims to investigate perioperative risk factors for postoperative morbidity and early mortality after pneumonectomy for thoracic malignancies. METHODS: We retrospectively analyzed all patients who underwent pneumonectomy for thoracic malignancies at our institution between 2014 and 2022. Complications were assessed up to 30 days after the operation. Mortality for any reason was recorded after 30 days and 90 days. RESULTS: A total of 145 out of 169 patients undergoing pneumonectomy were included in this study. The postoperative 30-day complication rate was 41.4%. The 30-day-mortality was 8.3%, and 90-day-mortality 17.2%. The presence of cardiovascular comorbidities was a risk factor for major cardiopulmonary complications (54.2% vs. 13.2%, p < 0.01). Postoperative bronchus stump insufficiency (OR: 11.883, 95% CI: 1.288-109.591, p = 0.029) and American Society of Anesthesiologists (ASA) score 4 (OR: 3.023, 95% CI: 1.028-8.892, p = 0.044) were independent factors for early mortality. CONCLUSION: Pneumonectomy for thoracic malignancies remains a high-risk major lung resection with significant postoperative morbidity and mortality. Attention should be paid to the preoperative selection of patients.